This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bone marrow failure occurs in the context of inherited genetic defects, various chronic inflammatory diseases or without the knowledge of a previous underlying condition. We recently demonstrated in a mouse model that lack of type I interferon (IFN)-signaling (IFNAR-/- mice) results in bone marrow (BM) depression. Lymphocyte-deficiency ( RAG-/- mice) does not affect hematopoiesis;however, lack of both lymphocytes and IFNAR (IFrag-/- mice) results in BM failure due to apoptosis of all lineages following Pneumocystis (PC) lung infection. This situation was also associated with loss of bone mass resulting in predisposition to bone fractures. Infection with other fungal pathogens, such as Cryptococcus, did not induce BM failure or significantly affect bone metabolism. The goal of this work is to understand mechanisms involved in BM failure in our system and how to prevent it. We found that lack of IFNAR-signaling resulted in increased oxidative stress in BM cells and also increased osteoclast activity following PC infection. This was associated with induction of BM cell apoptosis with specific induction of caspase-8 activity, which is the initiator caspase for the extrinsic apoptosis pathway. Kinetic studies revealed that signals between day 7 and day 10 post-infection appeared critical in determining the outcome of bone marrow responses. Quantitative RT-PCR demonstrated excessive upregulation of iNOS in BM cells from IFrag-/- mice compared to RAG-/- mice at day 7, significantly reduced expression of OPG, a decoy receptor for the apoptosis-inducing cytokine TRAIL and the osteoclast-differentiation factor RANKL, and down regulation of the anti-apoptotic factor BcL10. Based on these new data we propose that lack of type-I-IFN-signaling negatively affects the regulation of oxidative stress, and decoy mechanisms for TRAIL and RANKL in BM cells. This may negatively affect the hematopoietic cell environment and promote BM cell death following systemic responses to PC lung infection.